Contrast-Enhanced Breast Ultrasonography

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1 ME rticle ontrast-enhanced reast Ultrasonography Imaging Features With Histopathologic orrelation He Liu, MD, Yu-Xin Jiang, MD, Ji-in Liu, MD, Qing-Li Zhu, MD, Qiang Sun, MD, Xiao-Yan hang, MD Objective. The purpose of this study was to identify histopathologic correlates for the varied appearances of breast masses on contrast-enhanced ultrasonography (EUS). Methods. ontrast-enhanced ultrasonography was performed in 104 patients (age range, years) after administration of a sulfur hexafluoride microbubble contrast agent, and enhancement patterns were classified as no enhancement, peripheral enhancement, homogeneous enhancement, regional enhancement, and heterogeneous enhancement. ll patients histologic slides were reviewed and correlated with EUS findings. Results. In malignant masses, heterogeneous enhancement corresponded to tumor cell cords or clusters in a variable amount of desmoplastic stroma. Homogeneous enhancement corresponded to hypercellularity in the whole mass, or ductal carcinoma in situ (DIS) was predominant. Regional enhancement corresponded to a DIS component. Peripheral enhancement corresponded to a DIS component, hypercellularity or adenosis at the periphery, and low-degree cellularity, degeneration, fibrosis, or necrosis in the center. No enhancement was present in 1 case of low-grade DIS. In benign masses, heterogeneous enhancement corresponded to loose cell proliferation in a more sclerotic stroma. Homogeneous enhancement corresponded to diffuse hypercellularity, an inflammatory cell infiltrate, or intraductal papilloma. Regional enhancement corresponded to focal hypercellularity or intraductal papilloma within a dilated duct. No enhancement corresponded to desmoplastic stroma. Peripheral enhancement was shown in 1 case of granulomatous mastitis with an inflammatory infiltrate at the periphery and necrosis in the center. onclusions. reast mass EUS findings correlated with histologic features. Key words: breast neoplasm; contrast-enhanced ultrasonography; pathologic correlation. bbreviations EUS, contrast-enhanced ultrasonography; DIS, ductal carcinoma in situ; H&E, hematoxylin-eosin; ID, invasive ductal carcinoma Received March 5, 2009, from the Departments of Diagnostic Ultrasound (H.L., Y.-X.J., Q.-L.Z.), Surgery (Q..), and Pathology (X.-Y..), Peking Union Medical ollege Hospital, hinese cademy of Medical Sciences, eijing, hina; and Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania US (J.-.L.). Revision requested March 31, Revised manuscript accepted for publication pril 2, We thank Hanyuan Huang, MD, and Quancai ui, MD, for assistance. This research was supported by National Natural Sciences Foundation of hina grant ddress correspondence to Yu-Xin Jiang, MD, Department of Diagnostic Ultrasound, Peking Union Medical ollege Hospital, hinese cademy of Medical Sciences, 1 Shuaifuyuan, Wangfujing, eijing, hina. yuxinjiangxh@yahoo.com.cn ME rticle includes ME test New ultrasonographic techniques are being developed and studied. One such technique is contrast-enhanced ultrasonography (EUS), which has been studied to determine whether it is helpful for diagnosis. ontrast-enhanced ultrasonography has improved the ability of ultrasonography to characterize focal liver lesions. Several prospective studies have shown the comparability of this technique with contrast-enhanced computed tomography and magnetic resonance imaging for metastases, 1,2 and in some cases, lesions that are too small to detect with computed tomography or magnetic resonance imaging are clearly shown on EUS. The literature on EUS evaluation of breast masses is relatively scant and limited to 2009 by the merican Institute of Ultrasound in Medicine J Ultrasound Med 2009; 28: /09/$3.50

2 ontrast-enhanced reast Ultrasonography Doppler modalities, mainly studies of blood flow. 3 6 We previously published an article in which we reported on the same 104 patients as in this article. 7 In that article, breast EUS enhancement patterns were classified as no en - hancement, peripheral enhancement, homogeneous enhancement, regional enhancement, and heterogeneous enhancement. No enhancement pattern was suggestive of benignity, with sensitivity of 18.3%, specificity of 97.7%, a positive predictive value of 91.7%, a negative predictive value of 46.2%, and accuracy of 51.5%. The peripheral enhancement pattern was suggestive of malignancy, with sensitivity of 39.5%, specificity of 98.3%, a positive predictive value of 94.4%, a negative predictive value of 69.4%, and accuracy of 73.8%. Homogeneous, regional, and heterogeneous enhancement patterns did not show meaningful diagnostic information. To our knowledge, the correlation between EUS findings and pathologic features has not been well documented in large series of cases. The purpose of this study was to investigate the correlation of -mode pulse inversion harmonic EUS findings with histologic features in breast masses. Materials and Methods Patients This study design and protocol were approved by our Institutional Review oard, and all patients gave informed consent to be examined. From March 2005 to December 2005, 184 consecutive patients underwent conventional preoperative ultrasonography; 108 patients also underwent EUS. None of the masses were biopsied before the contrast studies. The inclusion criterion was the presence of masses on conventional ultrasonography. The exclusion criterion was contraindications to contrast agent administration. The contrast agent was not given if the patient had heart disease, pulmonary or respiratory disease, hypertension, or an allergy to the contrast agent or if the patient was pregnant or breastfeeding. ll patients underwent surgery (radical mastectomy with axillary dissection, n = 44; mastectomy, n = 2; or lumpectomy, n = 62) and had final pathologic diagnoses. Three of 108 cases were excluded because of poor image quality, and 1 was excluded because of missing histologic slides. s a result, 104 patients (age range, years; mean age, 44 years) were included in this study. The final pathologic diagnoses were invasive ductal carcinoma (ID; n = 35), ductal carcinoma in situ (DIS; n = 3), invasive lobular carcinoma (n = 3), mucinous carcinoma (n = 1), intraductal papillary carcinoma (n = 1), borderline phyllode tumors (n = 1), fibroadenoma (n = 30), adenosis (n = 15), intraductal papilloma (n = 9), granulomatous mastitis (n = 2), fat necrosis (n = 1), foreign body granuloma (n = 1), a cyst (n = 1), and hamartoma (n = 1). onventional and ontrast-enhanced Imaging Protocol HDI 5000 and iu22 systems (Philips Healthcare, othell, W) with a 12 5 MHz linear array transducer was used for conventional ultrasonography. n HDI 5000 system with a 7 4 MHz linear transducer and an iu22 system with an 8 4 MHz linear transducer were used for EUS. The contrast agent was SonoVue (racco Sp, Milan, Italy), which is a lyophilized powder of phospholipid-stabilized microbubbles containing sulfur hexafluoride gas with a mean diameter of 2.5 µm; the solution was reconstituted by the addition of 5 ml of sterile saline. -mode pulse inversion harmonic imaging was used for EUS, and the settings were as follows: the mechanical index was 0.06 to 0.08; the image depth was 3 or 4 cm; the single focus was at the bottom of the image; the probe was stabilized manually; and no pressure was exerted. One ultrasound physician (H.L., with 5 years of experience in breast ultrasonography) performed all conventional and EUS examinations. On conventional ultrasonography, the maximum imaging plane of the mass, which included the mass and its surrounding normal tissue if possible, was selected for EUS. fter a bolus injection of 2.4 ml of SonoVue manually via a 20-gauge cannula placed in the antecubital vein, the selected plane remained unchanged during the examination, and real-time imaging was recorded for up to 3 minutes. ll static and dynamic images were stored in the iu22 and HDI 5000 systems, and then single frames in the JPEG format and movie files in the Digital Imaging ommunications in Medicine format were exported to a personal computer. 912 J Ultrasound Med 2009; 28:

3 Liu et al Image nalysis To evaluate the enhancement pattern, microvascular imaging was created by QL software (Philips Healthcare) from a real-time contrastenhanced imaging sequence on a computer workstation. Microvascular imaging is composite imaging that is constructed through the summation of maximum-intensity pixels in consecutive imaging frames to improve visualization of tumor neovascularity. The captured imaging segment for microvascular imaging started when contrast washed in and ended when contrast began to wash out. This period lasted less than 30 seconds in all cases in our study, so motion artifacts were minimal. Two ultrasound physicians (H.L. and Q.-L.Z. by consensus) evaluated all ultrasonographic imaging without knowledge of the patients clinical data. ontrast-enhanced images were classified into 5 categories according to the distribution of enhanced areas of the mass: (1) no enhancement, with lack of enhancement after contrast agent injection (Figure 1, and ); (2) homogeneous enhancement, in which diffuse and homogeneous enhancement showed across the whole mass (Figure 2, and ); (3) peripheral enhancement, in which enhancing areas were only or more confined to the mass periphery (Figure 3, and ); (4) regional enhancement, in which part of a mass showed homogeneous enhancement (Figure 4, and ); and (5) heterogeneous enhancement, in which the mass was heterogeneously enhanced (Figure 5, and ). The difference between regional and heterogeneous enhancement was that the mass was classified as having regional enhancement if greater than 50% of the mass was enhanced homogeneously and classified as heterogeneous if less than 50% was enhanced homogeneously. Figure 1. Nonpalpable mass in the outer upper quadrant of the left breast in a 38-year-old woman. Surgical pathologic examination showed adenosis., onventional sonogram showing a hypoechoic mass of mm., ontrast-enhanced sonogram showing no enhancement., Pathologic specimen showing considerable fibrosis, distortion of the glands, and a dilated duct (H&E, original magnification 60). Histologic nalysis ll of the masses were removed intact without rupture and fixed. The specimens were fixed in formaldehyde, embedded in paraffin, cut into slices of 5-mm thickness parallel to the longest axis, and stained with hematoxylin-eosin (H&E). The histologic interpretations were performed by 1 pathologist (X.-Y.., with 8 years of experience in breast disease). maximal histologic section of each mass was selected for comparison J Ultrasound Med 2009; 28:

4 ontrast-enhanced reast Ultrasonography with the EUS image, which was obtained in the maximum imaging plane of the mass. For masses with no enhancement pattern or homogeneous enhancement, the pathologic features of the whole mass were noted. For masses with the peripheral enhancement pattern, the histologic findings of the tumor periphery and central area were respectively noted. For masses with the regional or heterogeneous enhancement pattern, the radiologist and pathologist compared EUS images and histologic slides in terms of masses localization and outlines, and the enhancing and nonenhancing areas were correlated with the corresponding areas in the pathologic specimens. Figure 2. Palpable mass in the upper quadrant of the right breast in a 47-year-old woman. Surgical pathologic examination showed ID., onventional sonogram showing a hypoechoic mass of mm., ontrast-enhanced sonogram showing diffuse homogeneous enhancement across the whole mass., Pathologic specimen showing solid tumor nests with little intervening stroma (H&E, original magnification 60). Results ll 104 masses were solid-appearing hypoechoic masses. Forty-three were malignant; 60 were benign; and 1 was borderline. The sizes of the malignant masses were 0.5 to 7.6 cm (mean, 2.4 cm), and 21(48.8%) were smaller than 2 cm. The sizes of the benign masses were 0.5 to 7.4 cm (mean, 2.2 cm), and 34 (56.7%) were smaller than 2 cm. There was no significant difference in tumor size between the malignant and benign masses (P =.398). Histologic Findings for Malignant Masses Invasive Ductal arcinoma (n = 35) Pathologic examination showed the following characteristics. In the 15 cases with peripheral enhancement, a high-grade DIS component or a higher degree of tumor cell proliferation compared with the central part appeared at the periphery (Figure 3); low-degree cellularity, degeneration, fibrosis, and necrosis were observed in the central tumor parts. In the 10 cases with heterogeneous enhancement, tumor cell cords were present in a variable amount of desmoplastic stroma (Figure 5). In the 5 cases with homogeneous enhancement, ID was characterized by solid tumor nests with little intervening stroma (Figure 2), or it was dominated by an extensive high-grade DIS component. In the 5 cases with regional enhancement, DIS corresponded to the enhanced area. 914 J Ultrasound Med 2009; 28:

5 Liu et al Figure 3. Palpable mass in the inner upper quadrant of the left breast in a 52-year-old woman. Surgical pathologic examination showed ID., onventional sonogram showing a hypoechoic mass of mm with an irregular margin., ontrastenhanced sonogram showing enhancement mainly confined to the periphery of the mass., Pathologic specimen showing a higher degree of tumor cell proliferation at the periphery compared with the central part (H&E, original magnification 60). Figure 4. Palpable mass in the inner upper quadrant of the right breast in a 42-year-old woman. Surgical pathologic examination showed adenosis., onventional sonogram showing a hypo - echoic mass of mm with a well-defined margin., ontrast-enhanced sonogram showing regional enhancement and homogeneous enhancement in part of the mass., Pathologic specimen showing focal hypercellularity corresponding to the enhanced area (H&E, original magnification 60). J Ultrasound Med 2009; 28:

6 ontrast-enhanced reast Ultrasonography Invasive Lobular arcinoma (n = 3) and Mucinous arcinoma (n = 1) On histopathologic review, invasive lobular carcinoma was characterized by a proliferation of tumor cells distributed in a single file ( Indian file ), with little disturbance of the background architecture. The only difference between the 1 case with peripheral enhancement and the 2 cases with heterogeneous enhancement was that adenosis rich in acinar and tubular structures was present at the periphery (Figure 6). In the 1 case of mucinous carcinoma with peripheral enhancement, the tumor cells dominated at the periphery of a mucous lake. Ductal arcinoma In Situ (n = 3) and Intraductal Papillary arcinoma (n = 1) Ductal carcinoma in situ and intraductal papillary carcinoma are solid-appearing hypoechoic masses on conventional ultrasonography, and the cystic changes in the papillary masses cannot be detected before contrast enhancement (Figure 7). One case of DIS with regional enhancement and 1 case with homogeneous enhancement were both intermediate grade, characterized by increased epithelial proliferation. The difference was that the DIS with regional enhancement was associated with sclerotic adenosis, which corresponded to the nonenhanced area. similar feature was also found in the case of intraductal papillary carcinoma with regional enhancement (Figure 7, and ). One case of DIS with no enhancement pattern was low grade and highly differentiated. In summary (Table 1), in malignant masses, heterogeneous enhancement corresponded to tumor cell cords or clusters in a variable amount of desmoplastic stroma. Homogeneous enhancement corresponded to hypercellularity in the whole mass, or DIS was predominant. Regional enhancement corresponded to a DIS component. Peripheral enhancement corresponded to a DIS component, hypercellularity or adenosis at the periphery, and low-degree cellularity, degeneration, fibrosis, or necrosis in the center. No enhancement was present in 1 case of low-grade DIS. Figure 5. Palpable mass in the outer upper quadrant of the left breast in a 56-year-old woman. Surgical pathologic examination showed ID., onventional sonogram showing a hypoechoic mass of 19 8 mm with internal blood flow., ontrastenhanced sonogram showing heterogeneous enhancement (arrows)., Pathologic specimen showing tumor cell cords present in desmoplastic stroma (H&E, original magnification 150). 916 J Ultrasound Med 2009; 28:

7 Liu et al Figure 6. Palpable mass in the inner upper quadrant of the left breast in a 51-year-old woman. Surgical pathologic examination showed invasive lobular carcinoma., onventional sonogram showing a hypoechoic mass of mm with an irregular margin., ontrast-enhanced sonogram showing enhancement mainly confined to the periphery of the mass (arrows)., Pathologic specimen showing adenosis rich in acinar and tubular structures at the periphery (H&E, original magnification 60). Figure 7. Palpable mass in the upper quadrant of the right breast in 60-year-old woman. Surgical pathologic examination showed intraductal papillary carcinoma., onventional sonogram showing a hypoechoic mass of 12 9 mm., ontrast-enhanced sonogram showing regional enhancement (arrows)., Pathologic specimen showing intraductal papillary carcinoma associated with sclerotic adenosis (H&E, original magnification 60). J Ultrasound Med 2009; 28:

8 ontrast-enhanced reast Ultrasonography Table 1. Histologic haracteristics of reast Lesions Enhancement Pattern Histologic haracteristics of Malignant Lesions Histologic haracteristics of enign Lesions No enhancement Low-grade DIS Desmoplastic stroma, fibrosis Homogeneous enhancement Diffuse hypercellularity or predominant DIS Diffuse hypercellularity, inflammatory cell infiltrate, or intraductal papilloma Peripheral enhancement DIS component, hypercellularity or adenosis at Inflammatory infiltrate at the periphery, necrosis the periphery, low-degree cellularity, degeneration, in the center fibrosis, or necrosis in the center Regional enhancement DIS component Focal hypercellularity or intraductal papilloma Heterogeneous enhancement Tumor cell cords in a variable amount of Loose cell proliferation in a more sclerotic stroma desmoplastic stroma Histologic Findings for enign Masses Fibroadenoma (n = 30) The 28 cases of fibroadenoma with heterogeneous enhancement showed a more sclerotic stroma characterized by low to moderate cellularity or hyalinization. The 2 cases of fibroadenoma with homogeneous enhancement revealed increased stromal cellularity and epithelial hyperplasia. denosis (n = 15) The 8 cases of adenosis with no enhancement pattern showed considerable fibrosis and distortion of the glands (Figure 1). The 6 cases of adenosis with heterogeneous enhancement were characterized by loose proliferation of acini or tubules. The 1 case of adenosis with regional enhancement showed focal hypercellularity corresponding to an enhanced area (Figure 4). Intraductal Papilloma The 3 cases of intraductal papilloma with regional enhancement and 5 cases with homogeneous enhancement revealed branching papillary fronds with fibrovascular cores; the difference was that intraductal papilloma with regional enhancement was within a cystically dilated duct, which corresponded to the nonenhanced area. The 1 case of intraductal papilloma with no enhancement pattern was probably due to its small size (3 mm) and hyalinization within the fibrovascular stalk. Granulomatous Mastitis (n = 2) One case of granulomatous mastitis with homogeneous enhancement showed a diffuse inflammatory infiltrate; the other case of granulomatous mastitis with peripheral enhancement revealed an inflammatory infiltrate at the periphery and necrosis in the center. Other One case of fat necrosis and 1 foreign body granuloma showed no enhancement pattern. One case of hamartoma showed heterogeneous enhancement. One cyst showed heterogeneous enhancement because of its thickened wall and multiple septations. One borderline phyllode tumor showed heterogeneous enhancement. In summary (Table 1), in benign masses, heterogeneous enhancement corresponded to loose cell proliferation in more sclerotic stroma. Homogeneous enhancement corresponded to diffuse hypercellularity, an inflammatory cell infiltrate, or intraductal papilloma. Regional enhancement corresponded to focal hypercellularity or intraductal papilloma within a dilated duct. No enhancement corresponded to desmoplastic stroma. Peripheral enhancement was shown in 1 case of granulomatous mastitis with an inflammatory infiltrate at the periphery and necrosis in the center. Discussion ontrast-enhanced ultrasonography was first used in breast imaging to increase the diagnostic accuracy of color or power Doppler imaging. 3 6 This was mainly due to improved visualization of the intratumoral vascular architecture after contrast agent administration. Different timeintensity curves were found for malignant and 918 J Ultrasound Med 2009; 28:

9 Liu et al benign breast masses. 8,9 Recent research has focused on -mode pulse inversion harmonic imaging with the use of the contrast agent SonoVue, which shows neovascular morphologic features by depicting microvessel perfusion. Recent research results have revealed some new characteristics of breast masses. 10,11 However, most of them did not correlate EUS findings with histopathologic features. In this study, we classified EUS enhancement patterns as no, homogeneous, peripheral, regional, and heterogeneous enhancement and correlated them with histopathologic features. Our preliminary results show that enhanced areas correspond to intraductal carcinoma, invasive carcinoma, intraductal papilloma, fibroadenoma with increased stromal cellularity and epithelial hyperplasia, adenosis rich in acinar and tubular structures, or an inflammatory cell infiltrate; nonenhanced areas correspond to low cellularity, desmoplastic stroma, dilated ducts, degeneration, fibrosis, or necrosis. The clinical applicability of this method is now limited, but the information will be valuable in enhancing further research projects to see whether EUS is helpful for diagnosis, biopsy, and therapy in the future. onventional ultrasonography for evaluating treatment responses based on tumor size measurement has limited efficiency because a therapeutic effect may not lead to a clear reduction in size, particularly in the period immediately after therapy. review of the literature reveals that conventional ultrasonography may overestimate or underestimate residual tumors Herrada et al 14 found that final histologic results correlated with conventional ultrasonographic findings in only 66.3% of cases. Observation of changes in contrast enhancement patterns on EUS may be useful in evaluating patients responses to therapy because of their correlation with histopathologic features. Our study had the following limitations. The correlation between EUS findings and histo - pathologic features was studied in the imaging plane of the maximum tumor diameter, but it would have been better to study each tumor in its entirety. In addition, the enhancement pattern classifications were subjective, and sometimes it was difficult to differentiate between enhancement patterns. In conclusion, our study revealed that breast mass EUS findings correlated with histologic features. References 1. Dietrich F, Kratzer W, Strobe D, et al. ssessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus T and MRI. World J Gastroenterol 2006; 12: lbrecht T, Hoffmann W, Schettler S, et al. -mode enhancement at phase-inversion US with air-based microbubble contrast agent: initial experience in humans. Radiology 2000; 216: Forsberg F, Goldberg, Merritt R, et al. Diagnosing breast lesions with contrast-enhanced 3-dimensional power Doppler imaging. J Ultrasound Med 2004; 23: Moon WK, Im JG, Noh DY, Han M. Nonpalpable breast lesions: evaluation with power Doppler US and a microbubble contrast agent initial experience. Radiology 2000; 217: Yang WT, Tse GM, Lam PK, Metreweli, hang J. orrelation between color power Doppler sonographic measurement of tumor vasculature and immunohistochemical analysis of microvessel density for the quantitation of angiogenesis. J Ultrasound Med 2002; 21: Yang WT, Metreweli, Lam PK, hang J. enign and malignant breast masses and axillary nodes: evaluation with echo-enhanced color power Doppler US. Radiology 2001; 220: Liu H, Jiang YX, Liu J, Zhu QL, Sun Q. Evaluation of breast lesions with contrast-enhanced ultrasound using the microvascular imaging technique: initial observations. reast 2008; 17: Huber S, Helbich T, Kettenbach J, Dock W, Zuna I, Delorme S. Effects of a microbubble contrast agent on breast tumors: computer-assisted quantitative assessment with color Doppler US early experience. Radiology 1998; 208: izzatto G, hersevani R, Ralleigh G. ontrast media in ultrasonography: basic principles and clinical applications. In: Quaia (ed). reast. erlin, Germany: Springer; 2005: Furuse F, Forsberg F, Goldberg, et al. Pulse inversion harmonic imaging for breast cancer diagnosis. Ultrasound Med iol 2003; 29(suppl):S93 S assano E, Rizzo S, ozzini, Menna S, ellomi M. ontrast enhanced ultrasound of breast cancer. ancer Imaging 2006; 6: von Minckwitz G, osta SD, Eiermann W, et al. Maximized reduction of primary breast tumor size using preoperative chemotherapy with doxorubicin and docetaxel. J lin Oncol 1999; 7: J Ultrasound Med 2009; 28:

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